The overall goal of this research program is to establish a rational foundation for the combination chemotherapy of cancer. The approach is based on the concept of employing combinations of metabolites and antimetabolites to modulate biochemical pathways to achieve maximal cancer cell damage while simultaneously protecting normal host cells from drug toxicity. Much of the basic information which provides a rationale for a particular drug combination is based upon prior in vitro studies by other research groups. However, since the ultimate utility of a drug combination depends upon the selective achievement of the appropriate modulation(s) of biochemical pathways in vivo, studies in Research Project 2 will be designed to determine the biochemical effect of a given modulating agent on the final activity of the primary effector agent in vivo. Thus, promising therapeutic results from a particular drug manipulation obtained in Research Project 1 will be investigated at the biochemical level to confirm whether or not the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide new information for therapeutic studies that will be utilized to alter the drug combination or schedule so as to achieve the desired therapeutic effect. All comparative NMR and biochemical studies will be performed with tissues obtained from mice undergoing the in vivo therapeutic regimen in question. These in vivo biochemical, pharmacological and NMR studies will provide guidelines for comparative pharmacological, biochemical and NMR studies in the clinic (Research Project 3, Clinical Studies) which will be used to adjust dosage and scheduling of promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Projects 1 and 2, lead to guidelines for specific clinical trials; feedback from Project 3, Clinical Studies, may suggest new experimental studies and refinements.